Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase-2 (COX-2) with analgesic-antiinflammatory activity
Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase-2 (COX-2) with analgesic-antiinflammatory activity
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DOI：
10.1002/ddr.9
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发表时间：
2000-12-01
影响因子：
3.8
通讯作者：
Knaus, EE
中科院分区：
文献类型：
--
作者：
Habeeb, AG;Rao, PNP;Knaus, EE
合成了一组4，5-二苯基异恶唑（11 a-p）、3，4-二苯基-5-三氟甲基异恶唑（15，21）和4，5-二苯基-3-甲磺酰胺基异恶唑（23），它们在苯环的对位上具有多种取代基（H，F，MeS，MeSO，MeSO 2），用于评价作为镇痛剂和选择性考克斯-2抑制剂（Al）的活性。尽管化合物（11 a-p）的3，5-二苯基异恶唑基团显示出有效的镇痛和Al活性，但所评价的那些化合物（11 a，11 b，11 m）是比考克斯-2更有选择性的考克斯-1抑制剂，除了4-（4-甲磺酰基苯基）-5-苯基异恶唑（11 n）显示出2.1的适度的考克斯-2选择性指数（SI）。相反，3-（4-甲磺酰基苯基）-4-苯基-5-三氟甲基异恶唑（15）是一种高效、选择性的考克斯-2抑制剂，具有良好的镇痛和AI活性（考克斯-1 IC 50> 500 μ M;考克斯-2 IC 50 < 0.001 M），相对于参比药物塞来昔布，考克斯-2 SI> 500，000（考克斯-1 IC 50 = 22.9 μ M;考克斯-2 IC 50 = 0.0567 μ M），考克斯-2 SI为404。3-苯基-4-（4-甲磺酰基苯基）区域异构体（21）是一种效力较低的抑制剂（相对于区域异构体（15），考克斯-1 IC 50 = 252 μ M;考克斯-2 IC 50 = 0.2236（μ M），考克斯-2 SI为1122）。相关化合物4，5-二苯基-3-甲基磺酰胺基异恶唑（23）显示出相似的（与21）效力和考克斯-2选择性（考克斯-1 IC 50> 200 μ M;考克斯-2 IC 50 = 0.226 μ M），SI为752。对人考克斯-2酶活性位点中最有效和最具选择性的考克斯-2抑制剂（15）的分子模拟（对接）研究表明，C-5 CF 3取代基位于Tyr（355）酚OH的3.37埃处，Ser（530）OH的6.91埃处。MeSO 2取代基的S-原子位于考克斯-2二级口袋（瓦尔（523））内部深处（距离入口7.40埃）。这些研究表明，C-5 CF 3（15，21）或C-3 NHSO 2 Me（23）中心异恶唑环取代基对这类化合物选择性抑制考克斯-2至关重要。(C)2001 Wiley-Liss，Inc.
A group of 4,5-diphenylisoxazoles (11a-p), 3,4-diphenyl-5-trifluoromethylisoxazoles (15, 21), and 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) possessing a variety of substituents (H, F, MeS, MeSO, MeSO2) at the para-position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX-2 inhibitory antiinflammatory (Al), agents. Although the 3,5-diphenylisoxazole group of compounds (11a-p) exhibited potent analgesic and Al activities, those compounds evaluated (11a, 11b, 11m) were more selective inhibitors of COX-1 than COX-2, with the exception of 4-(4-methylsulphonylphenyl)-5-phenylisoxazole (11n) that showed a modest COX-2 selectivity index (SI) of 2.1. In contrast, 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (15), which retained good analgesic and AI activities, was a highly potent and selective COX-2 inhibitor (COX-1 IC50 > 500 muM; COX-2 IC50 < 0.001 M) with a COX-2 SI of > 500,000, relative to the reference drug celecoxib (COX-1 IC50 = 22.9 muM; COX-2 IC50 = 0.0567 muM) with a COX-2 SI of 404. The 3-phenyl-4-(4-methylsulphonylphenyl) regioisomer (21) was a less potent inhibitor (COX-1 IC50 = 252 muM; COX-2 IC50 = 0.2236 (muM) with a COX-2 SI of 1122, relative to the regioisomer (15). The related compound 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) exhibited similar (to 21) potency and COX-2 selectivity (COX-1 IC50 > 200 muM; COX-2 IC50 = 0.226 muM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX-2 inhibitor (15) in the active site of the human COX-2 enzyme showed the C-5 CF3 substituent is positioned 3.37 Angstrom from the phenolic OH of Tyr(355), and 6.91 Angstrom from the Ser(530) OH. The S-atom of the MeSO2 substituent is positioned deep (7.40 Angstrom from the entrance) inside the COX-2 secondary pocket (Val(523)). These studies indicate a C-5 CF3 (15, 21), or C-3 NHSO2Me (23), central isoxazole ring substituent is crucial to selective inhibition of COX-2 for this class of compounds. (C) 2001 Wiley-Liss, Inc.